Quinoline disulfides



Patented Nov. 11, 1947 UNITED STATES PATENT OFFICE 2,430,679QUINOLINEYDISULFIDES Glenn L. Jenkins, La Fayette, and John E.Christian, West Lafayette, Ind., assignors to Purdue ResearchFoundation, West Lafayette, Ind, a corporation of Indiana No Drawing.Application December 1, 1944, Serial No. 566,252

wherein R represents hydrogen, phenyl. benzyl, phenethyl radicals, alkylradicals having from 1 to 6 carbon atoms, or dialkyl amino alkylradicals whose alkyl groups have from 1 to 6 carbon atoms; R1 representshydrogen, benzoyl radicals or aliphatic acyl radicals having from 1 to 6carbon atoms; and R2 represents hydrogen, halogen, hydroxy, methoxy,ethoxy radicals, or alkyl radicals having from 1 to 6 carbon atoms. Inthe above formula the substituents may be located in any one of thepositions 2, 3, 4, 5, 6, 7, and 8 on each quinoline ring, there being nomore than one substituent at any of these positions at any one time.

The compounds of our invention are aminodiquinolyl disulfides whereinthe amino group itself may be substituted and additionally, othergroups, described as R2 above, may be substituted on the quinolinerings. It is to be noted however that the compounds are symmetrical. Forexample, if an amino group occupies a position on one quinoline ring itmust be correspondingly located on the other ring, and this symmetryapplies to all substituents. For example, in 5,5-diamino-6,6'-dimethoxy-8,8'-diquinolyl disulfide, which may berepresented by the following for- NHz HEN V 030 CH3 H30 0 it will beseen that the molecule is symmetrical and its symmetry is indicated inthe nomenclature by the use of prime numbers, these prime numbersindicating the same relative position in the second quinoline ring as inthe first quinoline ring.

The compounds of our invention are substantially stable compounds inthat they are not mula:

readily decomposed under ordinary conditions.

However, they may be reduced by strong reducing agents to yield thecorresponding thiols. In such reduction reaction, the sulfur-to-sulfurbond is broken and a hydrogen atom combines with each sulfur atom. Onthe other hand, under the action of strong oxidizing agents, thecompounds of our invention may be oxidized to sulfinic or sulfonicacids, provided that the amino groups are protected by certainsubstituents, for example, acetyl groups, in order to prevent attack ofthe oxidizing agent at the position of the amino groups on the quinolinerings.

The compounds of this invention possess basic properties, conferred bythe basic tertiary nitrogens in the quinolinev rings. The basicity isfurther increased if the amino groups are unsubstituted by acyl groups.Being basic, our compounds can readily form soluble acid addition saltssuch as the hydrochloride, the hydrobromide, and the sulfate.Additionally, insoluble acid addition salts may be prepared, such as theortho benzoylbenzoate and the dicyclohexyl sulfamate. In such acidaddition salts the acids combine with the two nitrogens of the quinolinenuclei, and also with the two amino groups when the latter areunsubstituted by acyl groups.

We may prepare our compounds in various ways. It is convenient, however,to use certain halogen substituted compounds as starting materials inthe synthesis. Thus, a substituted aminoquinoline halide may be reactedwith a metal disulfide whereby the halogen atom in the quinoline nucleusis substituted by sulfur. We may also prepare the compounds of ourinvention by reacting the substituted aminoquinoline halide with a metalhydrosulfide to obtain a substituted quinoline thiol which subsequentlymay be oxidized, by air or some other mild oxidizing agent, to thesubstituted diquinolyl disulfide.

When a substituted quinoline halide is used as a starting material inpreparing the above compounds, it should be noted that the halogen atomwhen located at any one of the positions 3, 5, 6, '7, and 8 of thequinoline nucleus is relatively inactive and will not readily react withmetal hydrosulfides or metal disulfides. It is therefore desirable tolocate within the molecule some group which has an activating effectupon the halogen. Among groups Which may be used for this purpose is thenitro group which when located in a position ortho or para to thehalogen atom has an activating effect on the halogen causing it to reactmuch more readily thereby making it more amenable to replacement. Thepresence of the nitro group thus may serve two purposes, namely,activating the halogen, and supplying the nitrogen for the amino group.However, the nitro group used for the activation of the halogen need notbe the source of the amino group. The nitro group may be replaced bychemical conversions to one of the groups which comprise R2, or afterhaving served its purpose as an activating agent may be completelyremoved from the quinoline ring by chemical means. 7

When the halogen is located in either of the positions 2 or- 4 on thequinoline nucleus, it is sufliciently reactive so that no activatinggroup is required.

An amino group which may be protected by some substituent may be presentin the halogen substituted molecule before reaction of the substitutedquinoline halide with a metal hydrosulflde or a metal disulfide, andafter the reaction has been carried out, it is a matter of choicewhether the amino group should be left protected or the protecting groupremoved to liberate the free amino group. It may be noted however thatthe requirement for an activating group in case the halogen atom islocated at any one of the points 3, 5, 6, 7, or 8 in the quinoline ringis not eliminated by the presence of an amino group or a substitutedamino group. It is only when the halogen is in the 2 or 4 position ofthe quincline ring that an activating group is unnecessary.

Among nitro compounds suitable for the synthesis of compounds of thisinvention in accordance with the generalizations given above may bementioned the following, which are listed with accompanying literaturereferences:

Chim. 4s,

Chim. 4'7,

Chim. 47,

Chim. 47,

7-chloro-8-nitroquinoline, Ann. Inst. Pasteur 44,

719 (1930) 2-chloro-6-nitro 4 methylquinoline, J. Chem.

Soc. (1930) 2346 2-chloro-3-nitro-4-ohloroquinoline, Ber. 51, 1500 Thefollowing examples illustrate compounds of our invention and methods ofpreparing the same.

Example 1 5,5-diamino-6,6'-dimethoxy-8,8' -diquinolyl disulfide,represented by the formula NH: HzN

CH2. H30 0 may be prepared by reacting 5-nitro-6-methoxy-8-chloroquinoline with sodium disulfide to produce 5,5'-dinitro6,6-dimethoxy 8,8'-diquinolyl disulfide, and reducing the nitro groupsof the 5,5 dinitro-6,6'-dimethoxy-8,8 diquinolyl disulfide to producethe desired compound in the manner indicated below;

20 g. of 5-nitro-6-methoxy-8-chloroquinoline are dissolved in about 250cc. of alcohol. This solution is refluxed, and 5.5 g. of sodiumdisulfide, dissolved in a minimum amount of water, are added slowly. Therefluxing is continued for two hours, the bulk of the alcohol removed byevaporation in vacuo, and the residue treated with an excess of water,whereupon a precipitate of a nitro compound, namely 5,5dinitro-6,6'-dimethoxy-8,8'-diquinolyl disulfide separates.

3 g. of the nitro compound, 5,5'-dinitro-6,6- dimethoxy-8,8'diquinolyldisulfide, are added to a solution of 12 g. of stannous chloridedissolved in 30 cc. of hydrochloric acid and the solution heated atabout C. for about one half hour. Upon cooling to about 0 C., aprecipitate of the tin double salt of S-amino-6-methoxy-8-quinolyl thiolseparates. This precipitate is filtered off, is treated with about 25cc. of 50 percent sodium hydroxide solution, and diluted to about cc.with water. About 10 g. of sodium bisulfite are then added to thesolution and. air passed through the solution, whereupon a precipitateof the desired 5,5 -diamino-6,6 -dimethoxy-8,8 -diquinolyl disulfideforms.

Example 2 6,6 diacetylamino- 2,2 diquinolyl disulfide, with thefollowing formula Example 3 6,6-dimethoxy 8,8 diamino-5,5-diquinolyldisulfide, with the following formula qjo on; H30 0 N N NH; HgN

may be prepared by reacting 5-ch1oro-6-methoXy-8-nitroquinoline withsodium disulfide to form 6,6 dimethoxy-8,8'-dinitro-5,5'-diquinolyldisulfide and reducin the nitro groups of the 6,6 -dimethoxy-8,8'-dinitro-5,5" -diquinolyl disulfide to produce the desired compound.Thus, 21 g. of 6-methoxy-8-amino-5-quinoline thiol are dissolved inabout 250 cc. of alcohol, and this solution refluxed. 5.5 g. of sodiumdisulfide, dissolved in a minimum amount of water, are added slowly. Therefluxing is continued for two hours. the bulk of the alcohol removed byevaporation in vacuo, and the residue treated with an eXceSs of water,whereupon a precipitate of 6,6-dimethoxy-8,8'-diamino-5,5-diquinolyldisulfide separates. 3 g. of this 6,6-dimethoxy-8,8-diamino-5,5-diquinoly1 disulfide are added to a solution of 12 g. of stannouschloride dissolved in 30 cc. of hydrochloric acid and the solutionheated at Example 4 6,6'-dimethoxy-8,8-diamino 4,4 diquinolyl disulfidewith the following formula HZN N H2 may be prepared by reacting4-chloro-6-methoxy-S-aminoquinoline with sodium disulfide in thefollowing manner:

20 g. of 4-chloro-6-methoxy-S-aminoquinoline and 5.5 g. of sodiumdisulfide are dissolved in about 250 cc. of 90 percent alcohol and theresulting solution refluxed for about six hours. The bulk of the alcoholis removed in vacuo and the residual solution treated with about 100 cc.of

N112 HzN O CH3 HsC O water and cooled to about 0 C. A precipitate of thedesired 6,6-dimethoxy-8,8-diamino-4,4'- diquinolyl disulfide separatesupon cooling of the solution.

We claim as our invention:

5,5'-diamino-6,6-dimethoxy 8,8 diquinolyl disulfide having the followingformula:

GLENN L. JENKINS. JOHN E. CHRISTIAN.

REFERENCES CITED The following references are of record in the 20 fileof this patent:

UNITED STATES PATENTS Name Date Scott Feb, 6, 1940 OTHER REFERENCESJour. Amer. Chem. Soc, vol. 62 (1940); pp. 173-174 and pp. 3508-3510.

Ber. Deut. Chem. Ges., vol. 32 (1899) p. 1305. Ber, Deut. Chem. Ger.,vol. 62 (1929); D. 2730.

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